Avascular necrosis of the femoral head in patients treated for leukaemia. Assessment of the need for a diagnostic protocol. / Necrosis avascular de cabeza femoral en pacientes tratados de leucemia. Evaluación de la necesidad de un protocolo diagnóstico.

OBJECTIVE: To evaluate the incidence of avascular necrosis of the hip in leukaemia patients treated in our hospital with high doses of corticosteroids in order to evaluate the necessity for an early detection protocol. MATERIAL AND METHODS: Observational-descriptive and retrospective study from 2005 to 2016 of 253 patients diagnosed with paediatric leukaemia. Patients with musculoskeletal pathology were identified and patients with avascular necrosis were analysed. RESULTS: A total of 26 patients (10%) had musculoskeletal symptoms. Three patients with avascular necrosis (1.2%) were analysed. One girl, 7 years old, was treated conservatively with traction - suspension and discharge. Two boys, an 11 and a 15.4 year-old,who developed graft-versus-host disease secondary to bone marrow transplantation, and whose treatment included high doses of corticosteroids, developed avascular necrosis of the hip. One was treated with bisphosphonates and forage and the other ended up with a total hip arthroplasty. DISCUSSION: The occurrence of musculoskeletal symptoms during the treatment of leukaemia is different according to the bibliographic series (0.43 -12.6%). Some authors observe an increased risk in female patients between the ages of 10 and 17. A retrospective study reveals that there is a delay of 3.9 months in the diagnosis of CAP since the onset of pain. Other authors relate NAV to loading joints, age and high doses of corticosteroids. CONCLUSION: Based on the low incidence of avascular necrosis of the hip in our 14-year-old population treated for leukaemia, the creation of diagnostic protocols seems not to be necessary. However, close monitoring of patients with potential risk factors recognized in the literature, is advisable.

Abandono del hábito tabáquico tras un primer ingreso en el Servicio de Neumología / Smoking cessation after first admission in a respiratory unit

Some authors suggest that hospitalization is an ideal moment to stop smoking. It is unknown the outcome of smokers admitted for the first time in the pulmonology department, which interventions are carried out to achieve smoking cessation and which are the dropout rates once they are discharged. The purpose of this study is to analyze the impact of a first hospital admission in a service of Pneumology on smokers. Epidemiological variables, smoking habit, specialized interventions carried out on these subjects and rate of withdrawal after discharge were studied. It is necessary to train specialists to diagnose and treat the patient in the process, so that on every hospitalized smoker a cessation intervention should be carried out.

Algunos autores defienden que el ingreso hospitalario constituye un marco ideal para dejar de fumar. Se desconoce lo que sucede con los fumadores que ingresan por primera vez en el Servicio de Neumología, sobre las intervenciones que en ellos se lleva a cabo, así como sus tasas de abandono una vez que son dados de alta. El objetivo de este estudio es analizar el impacto que tiene un primer ingreso hospitalario en el Servicio de Neumología en sujetos fumadores. Conocer sus variables epidemiológicas, el hábito de tabáquico, las intervenciones que el personal médico especializado realiza sobre estos sujetos y las tasas de abstinencia posteriores al alta. Es necesario formar a los especialistas para diagnosticar y tratar al paciente en dicho proceso, de tal forma que sobre todo sujeto fumador hospitalizado se realice alguna intervención.

[Withdrawal of artificial nutrition and hydration in severe stroke: medical, legal and ethical considerations]. / Aspects médicaux, législatifs et éthiques de l'arrêt de la nutrition et de l'hydratation artificielles dans l'accident vasculaire cérébral grave.

In the majority of cases, severe stroke is accompanied by difficulty in swallowing and an altered state of consciousness requiring artificial nutrition and hydration. Because of their artificial nature, nutrition and hydration are considered by law as treatment rather basic care. Withdrawal of these treatments is dictated by the refusal of unreasonable obstinacy enshrined in law and is justified by the risk of severe disability and very poor quality of life. It is usually the last among other withholding and withdrawal decisions which have already been made during the long course of the disease. Reaching a collegial consensus on a controversial decision such as artificial nutrition and hydration withdrawal is a difficult and complex process. The reluctance for such decisions is mainly due to the symbolic value of food and hydration, to the fear of "dying badly" while suffering from hunger and thirst, and to the difficult distinction between this medical act and euthanasia. The only way to overcome such reluctance is to ensure flawless accompaniment, associating sedation and appropriate comfort care with a clear explanation (with relatives but also caregivers) of the rationale and implications of this type of decision. All teams dealing with this type of situation must have thoroughly thought through the medical, legal and ethical considerations involved in making this difficult decision.

Substandard medicines in resource-poor settings: a problem that can no longer be ignored.

The circulation of substandard medicines in the developing world is a serious clinical and public health concern. Problems include under or over concentration of ingredients, contamination, poor quality ingredients, poor stability and inadequate packaging. There are multiple causes. Drugs manufactured for export are not regulated to the same standard as those for domestic use, while regulatory agencies in the less-developed world are poorly equipped to assess and address the problem. A number of recent initiatives have been established to address the problem, most notably the WHO pre-qualification programme. However, much more action is required. Donors should encourage their partners to include more explicit quality requirements in their tender mechanisms, while purchasers should insist that producers and distributors supply drugs that comply with international quality standards. Governments in rich countries should not tolerate the export of substandard pharmaceutical products to poor countries, while developing country governments should improve their ability to detect substandard medicines.

REACH: international prospective observational registry in patients at risk of atherothrombotic events. Results for the French arm at baseline and one year.

INTRODUCTION: Atherothrombosis is a systemic, diffuse disease associated with a high risk of cardiovascular morbidity and mortality. It is the main cause of death in Western populations, a major public health concern and its prevalence will further increase in the future. OBJECTIVES: To evaluate the rate of major vascular events at 1 year in French patients with confirmed atherothrombotic disease, recruited in the REACH international registry. METHODS: The REACH Registry has recruited 55.000 patients in 44 countries, aged at least 45 years and suffering from established atherothrombotic disease (EAD). In France, 713 investigators selected 3.514 patients with EAD between December 2003 and June 2004. Each investigator had to include 5 to 10 patients presenting after a first documented event of cerebrovascular disease (CVD), coronary artery disease (CAD) or lower limb peripheral arterial occlusive disease (PAD). The patients were followed up for 1 year with collection of major vascular events. RESULTS: Among the 3514 French patients with EAD in the REACH registry, 2.373 (68%) had documented coronary disease, 778 (22%) had an ischemic stroke and 923 (26%) had documented PAD. One quarter of CAD patients, one third of CVD patients and one half of PAD patients had another atherothrombotic disease localization. Follow-up at 1 year was documented for 3.373 patients with EAD. The 1-year event rate in patients who had EAD was a function of the number of atherothrombotic localizations: the vascular death rate was 1.8% if there was a single localization and 4.1% if there were 2 or 3 localizations, and the composite death, infarct and stroke rates were 3.8% and 7.2% respectively and 11.7% and 22.3% respectively if hospitalizations were added to the latter endpoint. CONCLUSION: The number of major vascular events during the first year is high in EAD patients although these patients were followed up on an outpatient basis and are considered to be stable. In patients with prior EAD, there was a close link between the incidence of major vascular events and the number of symptomatic arterial beds (2 or 3 sites). The risk of a major vascular event was twice as high in patients with polyvascular involvement than in those who only had one affected artery.

Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study.

OBJECTIVE: To determine the quality, and especially the dissolution properties of rifampicin, of fixed-dose combination (FDC) formulations of anti-tuberculosis agents manufactured by major market holders in the anti-tuberculosis sector and supplied for use in national tuberculosis control programmes. METHODS: Dissolution studies were performed for four formulations supplied by four different manufacturers in four dissolution media (0.1N and 0.01N HCl, phosphate buffer [PB] and 20% vegetable oil in PB), at four different agitation rates using USP apparatus II. The formulations were subjected to 4-week accelerated stability studies (40 degrees C / 75% RH) and evaluated for physical, chemical and dissolution stability. RESULTS: The formulations tested complied with pharmacopeial quality control (QC) tests. The extent of rifampicin release was independent of dissolution medium; however, a slight decrease in the dissolution rate was observed in two products. More than 75% of drug was released in 45 min at all agitation intensities except 30 rpm, and 20% oil in the medium reflected fed state. Formulations were stable in the packaging conditions recommended by the manufacturer for at least 4 weeks. CONCLUSIONS: The formulations tested passed the QC tests and were found to be stable. A decrease in the rate, although not the extent, of dissolution necessitated multiple point dissolution in gastric and intestinal pH conditions to ensure consistency in in vivo bioavailability.

[Systemic sarcoidosis revealed by acute ataxic sensory polyradiculoneuropathy]. / Sarcoïdose systémique révélée par une polyradiculonévrite aiguë sensitive ataxiante.

We present the case of a 35-year-old man who developed bilateral uveitis and acute ataxic sensorial polyradiculoneuropathy with sphincter dysfunction. The patient had multiple mediastinal adenopathies. Pathology examination led to the diagnosis of sarcoidosis. The patient improved partially spontaneously and totally after oral corticosteroid therapy. This case illustrates an unusual presentation of acute polyradiculoneuritis which is usually a predominantly motor disorder in sarcoidosis. Sensorial and ataxic neuropathy is uncommon. The course is more chronic and progressive.

[Hemiplegia and return to domicile]. / Hémiplégie vasculaire et retour à domicile.

OBJECTIVE: We have studied the outcome after a stroke on being discharged from a department of physical medicine and rehabilitation in patients with hemiplegia, and the factors influencing the choice of the orientation. MATERIAL AND METHOD: This prospective study was based on 93 patients. The mode of discharged was patient's domicile, institution, the number of death was also noted. The potentially influential factors studied were age, the side with hemiplegia, the aetiology of the hemiplegia, co-morbidity, the delay in starting rehabilitation, the neurological damage evaluated by the Orgogozo score, the initial functional damage evaluated by Functional Independence Measure (FIM) and by the functional score carried out within the framework PMSI(1) (computerised programme of medical care), the existence of aphasia, the existence of a depressive syndrome, presence of hemineglect, presence of superficial or profound sensory disorders, incontinence at the start of rehabilitation and at one month after the stroke, the existence of cognitive or psychiatric disorders. The tests used were the non-parametric test of Mann and Whitney, the chi(2) test and the correlation test. The threshold of significance used was 0.05. RESULTS: Based on 93 patients (47 women and 46 men, average age 64.8) 81 have gone back to their previous domicile, 11 were oriented toward an institution. One patient died. The predictive factors or those linked to an absence of return to the previous domicile were the age, social situation, the delay in starting rehabilitation, presence of aphasia, the initial and final functional damage, the impossibility to walk, the presence of a depressive syndrome, urinary incontinence. CONCLUSION: The authors stress the importance of familial environment and of functional independence in establishing a prognosis for return to the domicile.

Conditioning of ictal and interictal behaviors in rats by amygdala kindling: context as the conditional stimulus.

The authors showed that conditional effects of the stimulation environment modulate both the ictal and interictal behaviors of rats subjected to amygdala kindling. Rats received 53 stimulations to the left basolateral amygdala in 1 conditional stimulus (CS) context (CS+) and 53 sham stimulations (the stimulation lead was attached but no current was delivered) in another context (CS-), quasirandomly over 54 days. Three kinds of conditional effects were observed. First, after several stimulations, less ambulatory activity, more freezing, and less rearing reliably occurred in the CS+ context than in the CS-context. Second, after 45 stimulations, all of the rats chose the CS- context over the CS+ context in a conditioned place preference test. Third, when the rats were finally stimulated in the CS- context, their motor seizures were less severe: Latencies were longer, motor seizures were shorter, convulsive patterns were of a lower class, and there were fewer falls.

Conditioned effects of kindling.

Mild periodic electrical stimulation to any one of many brain sites leads to the development and progressive intensification of elicited motor seizures. Since its discovery in 1969, this kindling phenomenon has been widely studied both as a model of epileptogenesis and as a form of neuroplasticity, and recently there has been increasing interest in kindling as a model of the interictal (i.e. between-seizures) changes in emotionality that accompany certain forms of epilepsy. Despite the extensive use of the kindling model, little consideration has been given to the role played by the cues regularly associated with the delivery of the kindling stimulations. However, we have recently demonstrated that cues associated with the standard kindling protocol (e.g. the stimulation environment) produce conditioned effects on both the motor seizures and interictal behavior of rats and that some kindling sites, such as the amygdala, produce conditioned interictal behaviors that are defensive in nature. The implications that these findings have for the study of interictal behavioral changes in particular and to kindling research in general are discussed.

Laser relaxation-oscillation frequency imaging.

We describe a new imaging technique based on modification of laser relaxation frequency induced by coherent optical feedback from an external target. A direct comparison (both theoretical and experimental) is made with laser feedback interferometry techniques, in which there is a modification of the laser's steady state. We show that, for a laser with a cavity damping rate gamma(c) higher than the population damping rate, gamma(1) , the modification of the laser relaxation frequency can be several orders of magnitude more sensitive than the perturbation of the laser's output power. Application of this technique to imaging is reported.

Hunger, eating, and ill health.

Humans and other warm-blooded animals living with continuous access to a variety of good-tasting foods tend to eat too much and suffer ill health as a result--a finding that is incompatible with the widely held view that hunger and eating are compensatory processes that function to maintain the body's energy resources at a set point. The authors argue that because of the scarcity and unpredictability of food in nature, humans and other animals have evolved to eat to their physiological limits when food is readily available, so that excess energy can be stored in the body as a buffer against future food shortages. The discrepancy between the environment in which the hunger and eating system evolved and the food-replete environments in which many people now live has led to the current problem of overconsumption existing in many countries. This evolutionary perspective has implications for understanding the etiology of anorexia nervosa.

[The physiopathology of migraine]. / Physiopathologie de la migraine.

Although the neurobiological causative factors are now beginning to be understood, to a large extent the complex mechanisms involved in migraine remain an enigma, with the appearance of a transient unilateral cephalic pain, possibly preceded by a protean aura and associated with several other symptoms. The factors involved include three clinical signs or symptoms, i.e., pain, the aura (focalized neurological and neurosensory signs), and accompanying symptoms (e.g., sensory, psychological, or digestive); and three anatomical sites, i.e., the brain, the meningeal or intracranial vessel and a peripheral cranial nerve, the trigeminus (V). Familial hemiplegic migraine (FHM) has led to a consideration of the genetic origin of ionic channel-dependent pathologies (channelopathies), while certain other arguments which are for the most part indirect favor the hypothesis of abnormalities, again possibly of genetic origin, in the central neurotransmitters (including serotonin), which are involved in the transmission of pain messages and in vasomotor control. However, the main point is that each of the sites involved has its specific pharmacopoeia, which can contribute towards the treatment of migraine.

[Multiple cerebral infarcts associated with livedo secondary to anti-cancer therapy with interleukin 2 and interferon alpha]. / Infarctus cérébraux multiples associés à un livedo secondaires à un traitement anticancéreux par interleukine 2 et interféron alpha.

Anticancer drugs rarely cause strokes. We report the case of a woman treated for a kidney cancer by IL2 and IFN alpha, having developed multiple strokes associated with a livedo. The responsibility of IL2 and IFN alpha seemed likely. The association with a transitory livedo suggested that the pathological process might be a cerebral angiopathy with arterial vasospasms.

Reversible lesions of the rhinal cortex produce delayed non-matching-to-sample deficits in rats.

Rats with cannulae guides implanted in the rhinal cortex were tested on a delayed non-matching-to-sample task, following either lidocaine or sham microinfusions. Bilateral lidocaine microinfusions to the rhinal cortex produced significant delayed non-matching-to-sample deficits. These results are consistent with the putative role of the rhinal cortex in object recognition but because the deficits were not shown to be time dependent, non-mnemonic interpretations cannot be ruled out. These results also illustrate the utility of reversible lidocaine lesions in the study of the neuroanatomical basis of delayed non-matching-to-sample.

Maternal antibody transfer in baboons and mice vaccinated with a group B streptococcal polysaccharide conjugate.

Two animal models were used to study maternal transfer of antibody to a group B Streptococcus (GBS) type III polysaccharide-tetanus toxoid (III-TT) conjugate. The III-TT vaccine protected all 27 mouse pups born to vaccinated dams against a GBS challenge. In a separate study of vaccinated mouse dams and pups, maternal sera contained all 4 subclasses of polysaccharide-specific IgG, with IgG1 accounting for 83% of total IgG. Specific IgG subclass distribution (IgG1>>IgG2a=IgG2b=IgG3) in newborn pups closely resembled that in their mothers. Seven of 9 female baboons given the III-TT vaccine had 5- to 36-fold increases in specific antibody from baseline levels; they transferred 26%-185% of specific antibody to their offspring. Matched maternal and neonatal sera obtained at delivery were functionally equivalent in an in vitro opsonophagocytosis assay. These preclinical studies provide further evidence for effective immunogenicity of GBS conjugate vaccine and efficient transport of functionally active maternal antibody.

Requirements for anti-tuberculosis drug tender requests.

As more and more institutions and experts push for the use of fixed-dose combinations (FDC) of anti-tuberculosis drugs, the market will most probably change dramatically in the next few years. Prices should go down, but quality must remain an essential goal for managers in charge of the procurement process. General essential requirements for suppliers submitting for competitive bidding are reviewed, and in particular the WHO certification scheme. Even though the scheme does not dispense with the need to submit drugs to the quality control procedures required in the importing country, it is a very useful tool which should be encouraged in the supply process. Specific requirements for FDCs are discussed, particularly interpretation of the bioavailability tests which are compulsory for rifampicin-containing FDCs.

Rhinal cortex, but not medial thalamic, lesions cause retrograde amnesia for objects in rats.

Male Long-Evans rats were trained on five separate object discrimination problems at different times prior to surgery. Following surgery, retrograde amnesia was assessed by measuring retention of the preoperatively learned discrimination problems in lesioned rats and controls. Rats with rhinal cortex lesions displayed temporally graded retrograde amnesia; retention of object discriminations acquired in the recent past (i.e. 2 or 9 days prior to surgery) was significantly impaired, whereas retention of object discriminations acquired more remotely (i.e. 16, 37, or 58 days prior to surgery) was not. In contrast, rats with mediodorsal thalamic lesions exhibited normal savings of all discrimination problems. These results suggest that the rhinal cortex, but not the mediodorsal thalamus, plays a time-limited role in the consolidation of object memory.

Characterization of the defensive nature of kindling-induced emotionality.

Long-term amygdala kindling produces substantial changes in emotional behavior in rats. The purpose of these experiments was to determine whether kindling-induced emotionality is fundamentally defensive or aggressive in nature. In Experiment 1, amygdala-kindled rats tested as intruders in a resident-intruder paradigm preferred an active defense strategy (i.e., defensive upright stance, jump attacks), whereas the sham-stimulated rats preferred a passive defense strategy (i.e., freezing). In Experiment 2, amygdala-kindled rats explored an unfamiliar open field significantly less than did the sham-stimulated rats, and they were significantly more resistant to capture from the unfamiliar open field than were the sham-stimulated rats. In contrast, there were no significant differences between the kindled and sham-stimulated rats in resistance to capture from their home cages. These results suggest that the emotionality produced by long-term amygdala kindling is fundamentally defensive in nature.

Is orphan drug status beneficial to tropical disease control? Comparison of the American and future European orphan drug acts.

UNLABELLED: OBJECTIVES To quantify past outcomes of tropical pharmacology research and development (R & D) and to assess past benefits of the American orphan drug act and potential benefits of the future European orphan drug regulation on tropical diseases. METHODS: This paper presents two analyses: a 1983-97 retrospective study of the United States Orphan Drug Act concerning rare diseases and a prospective study of the European Proposal for a Regulation Concerning Orphan Drugs and its possible impact on tropical diseases. RESULTS: Different programmes have in the past tried to stimulate R & D in this area, but results remain limited. Of 1450 new chemical entities marketed between 1972 and 1997, 13 were specifically for tropical diseases and considered as essential drugs. Between 1983 & 1997, the US Orphan Drug Act approved 837 drugs and marketing of 152 new molecular entities (NMEs). Three NMEs have been designated for malaria and human African trypanosomiasis. Seven others, already commonly used in tropical diseases, received either orphan designation or an orphan approval for another indication. Pharmaceutical companies benefit from the US framework only when the US market exclusivity clause was applicable. Future European orphan drug regulation appears to be similar to the US Orphan Drug Act. CONCLUSION The orphan drug programmes relating to rare diseases have met with some success. Considering tropical diseases rare diseases seems inadequate to boost pharmaceutical R & D. However, some provisions of the European text may be relevant to tropical diseases, admitting the need for a more specific rule for evaluations of this kind of drug and recognizing the existence of 'diseases of exception'.